Deconstructing the peptide-MHC specificity of T cell recognition

Cell. 2014 May 22;157(5):1073-87. doi: 10.1016/j.cell.2014.03.047.


In order to survey a universe of major histocompatibility complex (MHC)-presented peptide antigens whose numbers greatly exceed the diversity of the T cell repertoire, T cell receptors (TCRs) are thought to be cross-reactive. However, the nature and extent of TCR cross-reactivity has not been conclusively measured experimentally. We developed a system to identify MHC-presented peptide ligands by combining TCR selection of highly diverse yeast-displayed peptide-MHC libraries with deep sequencing. Although we identified hundreds of peptides reactive with each of five different mouse and human TCRs, the selected peptides possessed TCR recognition motifs that bore a close resemblance to their known antigens. This structural conservation of the TCR interaction surface allowed us to exploit deep-sequencing information to computationally identify activating microbial and self-ligands for human autoimmune TCRs. The mechanistic basis of TCR cross-reactivity described here enables effective surveillance of diverse self and foreign antigens without necessitating degenerate recognition of nonhomologous peptides.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Amino Acid Sequence
  • Animals
  • Cross Reactions
  • HLA Antigens / immunology
  • HLA Antigens / metabolism
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Ligands
  • Mice
  • Models, Molecular
  • Peptide Library
  • Peptides / chemistry*
  • Peptides / immunology
  • Receptors, Antigen, T-Cell / chemistry*
  • Receptors, Antigen, T-Cell / immunology
  • T-Lymphocytes / chemistry
  • T-Lymphocytes / immunology*


  • HLA Antigens
  • Ligands
  • Peptide Library
  • Peptides
  • Receptors, Antigen, T-Cell

Associated data

  • PDB/4P2O
  • PDB/4P2Q
  • PDB/4P2R
  • SRA/SRP040021